Human colon cancer remains resistant to most chemotherapeutic agents. The goal of this Project is to develop and test rationale strategies for overcoming colon cancer alkylating agent resistance. We will conduct clinical trials of biochemical modulating agent based on the results of studies undertaken in human colon cancer cell lines, resistant to BCNU and melphalan, which are grown in vitro and in vivo in athymic mice. Alkylator resistance will be overcome by utilizing agents which modulate one or more of the following systems: pyridine nucleotide pools, poly(ADP-ribose) metabolism, thiol metabolism, calmodulin metabolism multi-drug resistance and of alkylguanine alkyltransferase. Modulating agents demonstrated effective in the laboratory will be studied in vivo in combination with BCNU and melphalan. Initially, we will determine the maximum tolerated dose and biochemical modulating dose of each modulator. Next, we will combine the modulator at a fixed dose (to achieve a desired biochemical or pharmacokinetic endpoint) with progressively higher doses of BCNU or melphalan, and will determine the interaction of these 2 classes of agents in studies of pharmacokinetics, toxicity, biochemical modulation, and anti-tumor effect. Later, we will optimize the anti-colon cancer effect by escalating the alkylating agents to higher doses which require autologous bone marrow rescue. Finally, we will validate this approach for colon cancer by conducting Phase II and III clinical trials.